Researchers Make Progress Engineering Digestive System Tissues

New proof-of-concept research at Wake Forest Institute for
Regenerative Medicine suggests the potential for engineering
replacement intestine tissue in the lab, a treatment that could be applied to
infants born with a short bowel and adults having large pieces of gut removed
due to cancer or inflammatory bowel disease.

Lead researcher Khalil N
Bitar, Ph.D., a professor at the institute, which is part of Wake Forest Baptist Medical Center,
reported the results this week at Digestive Diseases Week in Washington, D.C.
He also updated attendees on a related project to engineer anal sphincters for
patients with fecal incontinence.

“Results from both projects
are promising and exciting,” said Bitar. “Our latest effort, to find a new
solution for the urgent need for gut-lengthening procedures, shows we can meet
the basic requirements for regenerating segments of the gastrointestinal
tract.”

Both projects are based on using
a patient’s own cells to grow replacement tissue in the lab. Elie Zakhem, a
doctoral student in Bitar’s lab, is currently working on developing tissue-engineered
gut replacements. The researchers use smooth muscle and nerve stem cells from human
intestine to engineer innervated muscle “sheets.” The sheets are then wrapped
around tubular chitosan scaffolds. Chitosan is a natural biomaterial derived
from shrimp shells. The material is already approved by the U.S. Food and Drug
Administration for certain applications.

The tubular structures were
implanted just under the skin of rats for 14 days, a first step in assessing
their performance. Researchers found that the implants developed a blood vessel
supply and that the tube opening was maintained. In addition, the innervated
muscle “remodeled,” which means that the cells began the process of releasing their
own materials to replace the scaffold.

“It is the combination of
smooth muscle and neural cells in gut tissue that moves digested food material
through the gastrointestinal tract and this has been a major challenge in
efforts to build replacement tissue,” said Bitar. “Our preliminary results demonstrate
that these cells maintained their function and the implant became vascularized,
providing proof of concept that regenerating segments of the gastrointestinal
tract is achievable.”

The researchers’ next steps are
to develop the lining of the intestine that is responsible for absorption and
secretion. In a study involving research animals, they also plan to surgically
connect the replacement segments to native intestine to assess function.

The group’s second project,
to engineer anal sphincters, also reached a new milestone with the successful
implantation of the structures in rabbits.

“These bioengineered
sphincters, made with both muscle and nerve cells, restored fecal continence in
the animals throughout the six-month follow-up period after implantation,” he
said. “This provides proof of concept of the safety and efficacy of these
constructs.”

Sphincters are ring-like
muscles that maintain constriction of a body passage, such as controlling the
release of urine and feces. There are actually two sphincters at the anus – one
internal and one external. A large proportion of fecal incontinence in humans is
the result of a weakened internal sphincter.

“Many individuals find
themselves withdrawing from their social lives and attempting to hide the problem
from their families, friends and even their doctors,” said Bitar. “Many people
suffer without little help.”

To engineer the internal
anal sphincters, researchers used a small biopsy from the animals’ sphincter
tissue and isolated smooth muscle cells that were then multiplied in the lab.
In a ring-shaped mold, these cells were layered with nerve cells isolated from
small intestine to build the sphincter. The mold was placed in an incubator,
allowing for tissue formation. The entire process took about four to six weeks.

The bioengineered sphincters
mimicked the architecture and function of native tissue and there are no signs
of inflammation or infection after implantation. The constructs demonstrated
the presence of contractile smooth muscle as well as mature nerve-cell
populations.

“In essence, we have built a
replacement sphincter that we hope can one day benefit human patients,” said
Bitar. “Because these sphincters are made with both muscle and nerve cells, they
are ‘pre-wired’ to be connected with nerve pathways in the intestine.”

Bitar’s goal is to
eventually conduct studies of the technology in humans. He said the technology could
be applied to other diseases of the sphincter muscles, including urinary
incontinence.

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